FDA Guidance Finalizes Position on In Vitro Companion Diagnostic Devices

As more targeted therapies are developed – defined as treatment that block disease progression by interfering with specific molecules (aka molecular targets) involved in the many aspects that regulate disease proliferation (National Cancer Institute) – the population of patients for whom the therapy is safe and effective is narrowing. This trend is especially prevalent in the field of oncology.

To identify the subset of patients who will benefit from taking the targeted treatment, therapeutic companies can deploy a diagnostic test. The field of In Vitro Companion Diagnostics, which are tests that provide information that is essential for the safe and effective use of a corresponding therapeutic product, is growing exponentially alongside the general change in healthcare towards personalized medicine. Not surprisingly, regulatory agencies are stepping in to ensure that the use of such tests is closely monitored. In fact, the majority of Companion Diagnostic (CDx) assays are considered Class III medical devices, which by definition are generally the highest risk devices and are therefore subject to the highest level of regulatory control (FDA.gov). Putting oneself or one’s family member in the position of the patient, it is easy to see why one would want the test that ultimately guides treatment decisions to be thoroughly verified and validated.

FDA’s Position on In Vitro Companion Diagnostic Devices

On August 6, 2014 the Food and Drug Administration (FDA) released its final guidance for In Vitro Companion Diagnostic Devices. Guidance documents from FDA do not contain legally enforceable regulation; however they illustrate the Agency’s current perspective and therefore should be considered seriously by sponsor and diagnostic companies. The guidance describes the pathway that should be taken by “…(1) sponsors who are planning to develop a therapeutic product (either a novel product or an existing product with a new indication) for which the use of an in vitro companion diagnostic device (or test) is essential for the therapeutic product’s safe and effective use and (2) sponsors planning to develop an in vitro companion diagnostic device that is intended to be used with a corresponding therapeutic product”

There are two types of regulatory paths for CDx assays – tests are either granted Premarket Approval (PMA) or are 510K cleared. The FDA guidance indicates the regulatory path a new CDx will be required to take depends upon “…the risk together with available controls to mitigate risk.” Regardless which approval path the CDx takes, it is recommended the therapeutic and diagnostic be approved contemporaneously (so as one approval does not hold up the other). Although this situation is ideal, it is not always practical, and therefore it is important to bring in the appropriate partners to facilitate the simultaneous approval of the CDx and therapeutic as soon as the need is identified.

There are many steps in achieving approval of a CDx. For starters, the design of the assay is critical. A CDx must be sensitive enough such that it identifies the statistical majority of patients who have the molecular target in question. In addition, the test has to be specific enough that it only identifies those patients who will respond, and does not falsely identify patients who will not respond. Because a CDx assay will be manufactured and potentially distributed globally, development of the assay must ensure repeatable and reproducible results in varying laboratory conditions. Once the kit prototype is confirmed, the manufacture of the assay for distribution must be regulated so as to control for and mitigate any risk associated with batch effects, shipping, and storage. Finally, all components of the assay must also be FDA approved. For example, many of the CDx assays approved for oncology are molecular-based, meaning they examine the patient’s DNA or RNA. In that case everything – from the kit used for isolation of the DNA or RNA to the CDx assay itself to the platform the assay is performed on (e.g. quantitative real-time PCR machine) to the software that interprets the result – must also be FDA-approved. Adding in the multiple parties involved in development of a therapeutic and you have a lot of “cooks in the kitchen” that need to be organized to achieve contemporaneous approval. Therefore it is crucial to incorporate the CDx strategy early in the therapeutic development lifecycle. To this end the FDA guidance recommends sponsors consult with the relevant review divisions to solicit pre-submission feedback as early as possible to ensure a coordinated effort for approval.

There are many benefits to utilizing CDx assays during drug development.

  • It’s Required: Depending on the nature of the therapeutic, the FDA may reject approval of the drug unless there is an associated diagnostic.
  • Shortened Timelines: Enrichment of target populations with a diagnostic facilitates rapid accrual of the “right” patients.
  • Decreased Risk: Enrolling the right patient population may mitigate risk throughout the clinical trial process.

For further reading, here are some examples of approved therapeutic/diagnostic pairs.

Medelis has partnered with Insight Genetics to help sponsors bring more effective cancer treatments to market and improve the lives of cancer patients. Contact us to learn more.

Medelis thanks Rachel L. Skelton, PhD, Regulatory Scientist at Insight Genetics, for the content of this post.